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In patients with oral or oropharyngeal cancer the functionality of the tongue may become severely affected by the treatment of the cancer. In order plan tongue cancer treatment with minimal loss of functionality, the patient’s tongue functionality after treatment can be estimated by biomechanical modelling. This model is constructed from post-mortem data of a different individual. However, the biomechanical model should be personalised using information of the tongue’s muscular architecture in order to better estimate the port-treatment functionality. Therefore, we applied the MRI method constrained spherical deconvolution (CSD) to the tongue, which resulted in accurate in-vivo reconstructions of the tongue’s muscular architecture. Subsequently, using a CSD-based registration algorithm we generated population averages of CSD images of in-vivo tongues. These averages served as the template from which we were able to automatically generate personalised biomechanical models of the tongue. These models predicted the range-of-motion of the tongues more accurately than a generic model. Although promising, the largest draw-back of CSD MRI is the long scan time, which increases the chance of motion artefacts distorting the images. Therefore, we designed and built a custom MRI receiver coil for tongue imaging. Using this coil, we were able to halve the scan time of a CSD scan. Furthermore, this acceleration provided by the custom coil allowed us to develop a real-time MRI sequence, resulting in three-dimensional videos of swallowing at a frame rate of 12 frames per second.

Salivary gland tumor research is hampered by low incidence and high diversity of tumors. By using nationwide data and a new imaging technique, some problems can be bypassed.In this thesis, some epidemiological questions were answered, regarding salivary gland pleomorphic adenoma (SGPA) incidence, recurrence rate and risk of malignant transformation in 3.506 Dutch patients. Subsequently, in a systematic review on natural history of recurrent pleomorphic adenoma, 9.003 Dutch and Danish patients were analyzed. The third paper for the first time reported all steps of malignant transformation of SGPA on a genetical level. In a paper on the risk of breast cancer after salivary gland cancer or SGPA, an increased risk in both cases was reported, based on Dutch data in over 3.600 patients.The second part of the thesis first systematically described the use of molecular imaging of salivary glands based on presence of prostate-specific membrane antigen (PSMA). Subsequently the potential use of PSMA PET/CT for head neck radiotherapy is described by showing how it can assess and guide salivary gland radiotherapy. Finally, presence of a large bilateral macroscopic collection of salivary gland tissue in the human nasopharynx was suspected on PSMA PET/CT, histologically and radiologically described and 3D-reconstructed in human cadaver tissue (n=2) and PSMA PET/CT scans of 100 patients. The gland collections were named “tubarial glands”. Subsequently, the effect of radiotherapy on these glands in 723 patients with head and neck cancer was evaluated, showing increased xerostomia and dysphagia. The paper was discussed is several published comments.

This thesis provides new insights in diagnostics and therapy of cutaneous head and neck melanoma. The concept of cutaneous melanoma treatment has changed significantly over the past two decades. The first part of this thesis, entitled ‘Diagnostics’, focuses on the evaluation of the new 8th AJCC cancer staging manual, including the application of new technologies in sentinel lymph node biopsy and selection of prognostic factors for individualized treatment. Improved knowledge of molecular biology, especially in the field of cancer immunology, has contributed to the innovative designs of curative immunotherapy trials in stage III cutaneous melanoma patients. This potentially curative treatment option positions the role of therapeutic regional dissections from a different perspective, marked by a shift from extensive dissections to more limited salvage operations for removal of residual lymph node metastases. The second part of this thesis, entitled ‘Therapy’, focuses on the value of standard curative surgical protocols for stage III head and neck cutaneous melanoma and on the role of new oncolytic immunotherapy in stage III-IV cutaneous melanoma. This thesis seeks to increase awareness of the effects of diagnostics and limited surgery in the pre-immunological era.

This thesis offers a detailed analysis of nodal disease characteristics in a large cohort of 3664 differentiated thyroid cancer patients managed at a single quaternary cancer institution. Developments in imaging technology have resulted in increased use of neck ultrasound to detect nodal disease. We demonstrate that preoperative neck ultrasonography has resulted in more comprehensive neck dissections and reduced salvage neck dissections in thyroid cancer. Details of prognostic nodal features are analyzed to stratify outcomes. Lymph node characteristics, particularly presence of extracapsular nodal spread and high lymph node burden are predictors of poorer outcome. Significantly improved nodal recurrence outcomes are reported in a modern cohort of differentiated thyroid cancer patients. The need for risk-stratified and cost-effective surveillance approaches to patients is addressed in the context of increasing thyroid cancer diagnosis around the world.This is a detailed study of lymph node metastases in thyroid cancer. The increased understating of nodal prognostic features dictates more accurate risk stratification, subsequent individualized management, and more cost-effective long-term surveillance.

This thesis shows the complexity and multidimensional concept of quality of care in head and neck cancer. The selected topics represent examples of quality assessment using structure [centralization (Chapter 2) and variation of care (Chapter 3)], process [waiting time (Chapter 4) and pathologic specimen handling (Chapter 5, 6)] and outcome indicators [influence of volume and variation of care on outcome (Chapter 3) and specific outcome of rare head and neck tumors arising in the salivary gland (Chapter 7, 8)]. Head and neck cancer care in the Netherlands is centralized in specific head and neck cancer centers, but nonetheless the care given varied per head and neck center. We showed that volume may play a role in this variation, but several other quality related aspects of head and neck cancer care are of influence as well. For instance: waiting time differences, as we showed that waiting time has significant influence on outcome. What we also showed is that pathology specimen handling is another key factor, and that non-standardized workflow leads to differences and non-uniformity.For the more rare types of head and neck cancer, like salivary gland tumors, the low volume in the Netherlands makes quality assurance almost impossible. For proper quality assessment and thereby quality assurance, based upon this thesis, redistribution of rare head and neck cancers appears inevitable. The variation in numbers and treatment we found could have been biased by case-mix factors we did not include. The relatively small sample size of our study population limited us regarding some statistics.

The work described in this thesis shows how intraoperative lesion identification can be improved via the introduction of (hybrid) tracers and optimised (hybrid) imaging modalities capable of detecting this tracers. In part one, the reader is introduced to the concept of fluorescence image-guided surgery and the evolution thereof. Furthermore the hybrid approach for image-guided surgical guidance is presented. Part two describes the clinical evaluation of the hybrid approach using the hybrid tracer indocyanine green-technetium 99m-nanocolloid. To further refine the hybrid approach for surgical guidance, part three of this thesis describes the development and evaluation of different types of (hybrid) imaging modalities.

Ototoxicity is a common adverse event after cisplatin treatment and radiotherapy to the head and neck area. Counseling patients about this adverse event is important. The thesis main objective is to improve our knowledge ototoxicity in patients with head and neck cancer. A systematic review showed that it is impossible to draw unambiguous conclusions about the incidence of (C)RT-induced ototoxicity, since different definitions of ototoxicity are used in the literature. Existing standards to score hearing impairment are available, but not consistently used. By developing a new grading system we facilitate a nuanced system, that may be used to assess the impact of hearing loss in specific situations in daily life. Furthermore, we developed a model to predict the treatment-induced hearing loss per individual. Based on pre-treatment hearing levels, radiation dose, and cisplatin dose, the model predicts the post-treatment hearing level at PTA 1-2-4 kHz. This model is a step towards improving counseling of patients. In a long-term follow-up study we found significant CRT-induced hearing loss at long-term. Patients treated with CRT intra-arterial showed significantly less hearing loss at both short-term and long-term post-treatment measurements compared to patients treated with CRT intravenous. Another follow-up study showed that patients treated with IMRT suffer from modest treatment-induced hearing loss, provided that the radiation dose to the cochlea is limited. In a study regarding hearing loss due to radiotherapy for head and neck rhabdomysarcoma in children, we concluded that 19% developed clinically relevant hearing loss at speech frequencies. Less hearing loss was seen after AMORE-based treatment compared to EBRT-based treatment.

In de afgelopen decennia zijn er opmerkelijke veranderingen opgetreden in de epidemiologie van het plaveiselcelcarcinoom in het hoofd-halsgebied (HNSCC). Naast de typische HNSCC patiënt (man, 60-70 jaar, nicotine- en alcohol-abusus) is er meer aandacht gekomen voor de jonge HNSCC patiënt (

The goal of this thesis was to find biomarkers through gene expression profiling, using microarray techniques, which can predict outcome after concurrent chemoradiation in head and neck cancer. The main endpoints for outcome were local control, locoregional control and disease free survival.

Om te kunnen beoordelen of een kwaadaardige vorm van huidkanker (melanoom) is uitgezaaid, kan de zogeheten schildwachtklier (de eerste klier waar uitgezaaide cellen vanuit de tumor naar toe gaan) worden verwijderd. Belangrijkste doel van de schildwachtklierprocedure is het identificeren van patiënten met uitzaaiingen in de lymfeklieren, zodat deze vroegtijdig aanvullend behandeld kunnen worden. De procedure blijkt niet te leiden tot lokale uitzaaiingen. Volgens Hidde Veenstra kan wellicht overwogen worden om aanvullend lymfeklieronderzoek achterwege te laten bij patiënten met minimale uitzaaiingen in de schildwachtklier. Aanvullende beeldvorming met SPECT-CT verbetert de procedure nog verder. Veenstra bracht ook lymfedrainagepatronen van melanomen in hoofd-halsgebied en romp in kaart. Er bestonden twijfels over deze methode omdat kort na de introductie in 29 procent van de gevallen de uitzaaiingen niet werden opgemerkt. Dat percentage is ondertussen gedaald tot drie procent. Volgens Veenstra was er sprake van een leerfase die nodig was om de techniek goed onder de knie te krijgen.

Well differentiated thyroid cancer is increasing in incidence. Despite the fact that more patients present with disease, deaths due to disease remain stable, as this malignancy is rarely fatal. The vast majority of patients can be cured, and even those that suffer a recurrence can often still expect to be disease free following salvage therapy. This thesis analyzes the outcomes of patients who present with well differentiated thyroid cancer. We report the factors which predict outcome within this group, and the mode of death for patients who recur and die of disease. We also report the results of treatment, with a particular focus on the role of individually selective therapy. Both surgical and non surgical treatments are analyzed in an attempt to define a balanced approach to the management of patients with this generally low risk disease.

In this thesis the current national and international practice and clinical decision-making process about functional inoperability are evaluated. An impression is drawn of which clinicians already apply the concept in practice, and which surgical procedures are being considered as functional inoperable. The decision-making process concerning functional inoperability appears subjective and variable, with evident geographical differences. The first step in objectifying functional inoperability has been taken by development of the cine MRI of swallowing and a dynamic model of the oral cavity and oropharynx.

Founded on Halsted’s hypothesis of sequential tumor spread, selective biopsy of the tumor draining lymph nodes enables early detection of clinically occult nodal metastases while sparing patients the morbidity of an unnecessary lymph node dissection. Originally introduced for melanoma and breast cancer, the sentinel node (SN) biopsy is a multidisciplinary diagnostic procedure based on the injection of a radiocolloid followed by lymphatic mapping using lymphoscintigraphy and SPECT/CT to identify the SNs. Intraoperatively, SNs are traditionally localized using a gamma ray detection probe and a separate injection of blue dye to visualize the SNs. Over the last decade, the procedure has expanded to malignancies with lymphatic drainage to areas of more complex anatomy or located deeply in the abdomen. SN biopsy in these patients may be challenging and may benefit from additional intraoperative tools. This thesis focuses on the clinical introduction of novel multimodal approaches in order to help optimize the SN procedure.

De behandelingstechniek Mohs’ micrografische chirurgie (MMC) heeft de voorkeur bij agressieve tumoren op neus en oogleden, terwijl voor tumoren op voorhoofd en wang conventionele excisie (CE) een goed alternatief vormt. Dit concludeert Paul van der Eerden. Hij bespreekt tevens innovatieve en minder complexe reconstructieve technieken die leiden tot goede cosmetische en functionele resultaten met minder belasting voor de patiënt. Van der Eerden vergeleek de resultaten van MMC en CE, twee behandelingstechnieken bij huidkanker, om tot een betere behandelkeuze te komen. Dat is belangrijk gezien de enorme toename van het aantal gevallen van huidkanker in Nederland.

De zorg voor patiënten met nasopharynxkanker in Indonesië is op dit moment erg teleurstellend. Maarten Wildeman noemt in zijn promotie verschillende oplossingen om de zorg te verbeteren zoals de implementatie van een datamanagementsysteem, opleiding van huisartsen voor een betere bewustwording en kennis van nasopharynxcarcinoom en introductie van nieuwe behandelingsmethoden. Nasopharynxcarcinoom, een kwaadaardige tumor in de keel-neusholte, is zeldzaam in de westerse wereld, maar komt veel voor in Indonesië. De ziekte is goed te genezen met radiotherapie in combinatie met chemotherapie, maar in Indonesië zijn de behandelresultaten teleurstellend. Wildeman onderzocht de mogelijke oorzaken van de teleurstellende behandelresultaten. Tevens testte hij het effect van training voor huisartsen, tijdens de training kregen huisartsen uitleg zodat ze in de toekomst patiënten sneller zullen verwijzen.